DESCRIPTION UCP3 is a novel uncoupling protein that is highly expressed in skeletal muscle and that has been genetically linked to fatty acid oxidation, obesity and type 2 diabetes in humans. As an uncoupler of oxidative phosphorylation, UCP3 has the potential to regulate energy metabolism. The purpose of this research is to determine the role of UCP3 in regulating muscle substrate utilization. Recent data indicate that changes in muscle UCP33 mRNA expression correlate positively with metabolic shifts in muscle fatty acid uptake and oxidation. Fatty acids and their derivatives modulate various cellular processes and must therefore by tightly regulated to maintain cell integrity and function. Several disease states, including obesity and type 2 diabetes, are associated with increased cell concentrations of fatty acids and their derivatives, suggesting that failure to adequately regulate cell fatty acid concentrations may have pathological consequences. We hypothesize that by stimulating beta-oxidation during states when fatty acids and toxic intermediates. Since muscle lipid accumulation has been linked to insulin-resistance, we also predict that muscles lacking UCP3 may be insulin resistant. The specific aims of this study are to: 1) determine whether muscle UCP3 specifically factors fat oxidation over that of glucose, 2) identify pathophysiological implications of absent UCP3 (e.g. insulin resistance) and 3) identify protective effects of increased UCP3. We will address these aims by examining the metabolic effects of absent UCP3 in muscles from UCP3 knock-out mice, and the metabolic effects of increased UCP3 in myocytes that over-express UCP3.